Recommends that multiple steps must be taken before ethical pediatric anthrax vaccine trials can be considered by the U.S. government

March 19, 2013

WASHINGTON, D.C. – In a report released today, the Presidential Commission for the Study of Bioethical Issues concluded that the federal government would have to take multiple steps before anthrax vaccine trials with children could be ethically considered. The Bioethics Commission was responding to a request from Health and Human Services Secretary Kathleen Sebelius who last year asked the members to study the question of anthrax vaccine trials with children after receiving a recommendation from another federal committee that such research be initiated, pending ethical review.

“The safety of our children is paramount and we have to get this precisely right,” said Commission Chair Amy Gutmann, Ph.D. “The Bioethics Commission concludes that many significant steps would have to be taken, including additional minimal-risk research with adult volunteers, before pediatric anthrax vaccine trials prior to an attack should be considered."

A major ethical consideration in “pre-event” trials, in which testing occurs before an actual or imminent attack, is that children do not stand to benefit directly from participating in the study, and so risk must be kept very limited and small. In addition to recommending that pre-event trials with children not go forward in the absence of further testing on adults, the Bioethics Commission clarifies other rigorous conditions that must be met before such pediatric research may ethically proceed.

“Out of respect for every individual, our nation must protect children enrolled in research studies while also doing its best to develop the knowledge needed to save children’s lives during a possible emergency,” Gutmann said.

In the report, Safeguarding Children: Pediatric Medical Countermeasure Research, the Bioethics Commission also more generally considered the ethics of research on pediatric medical countermeasures (MCM), the catchall term for the use of federally-regulated drugs and products in response to chemical, biological, radiological, and nuclear attacks.

Background:

In 2011, the U.S. government conducted a bioterrorism preparedness exercise to study the likely results of a large-scale release of weaponized anthrax spores in a city such as San Francisco. The casualty estimates were staggering: almost 8 million citizens would be affected, nearly a quarter of them children.

If such an event were to occur, current federal plans call for immediate distribution of antibiotics proven effective in treating anthrax infections, and a follow-up widespread vaccination program using Anthrax Vaccine Adsorbed (AVA). Vaccination is believed necessary because anthrax spores would likely continue to pose a threat of infection long after the initial release had taken place. AVA administration is challenging, however, because there is no definitive understanding of its effect in children despite having been in commercial production for more than four decades and having been safely administered to more than a million adults in the military.

After the 2011 bioterrorism exercise, the National Biodefense Science Board (NBSB) recommended that the U.S. government conduct a study to test the safety and effectiveness (“immunogenicity”) of AVA in children before an anthrax attack occurs, contingent upon a review of the ethical issues. Secretary Sebelius called on the Bioethics Commission for a thorough ethical review.

“The Bioethics Commission recognizes both the federal government’s fundamental duty to protect individual children from undue risk during research and its obligation to protect all children – as far as ethically and practically possible – during an emergency by being prepared,” said Daniel Sulmasy, M.D., Ph.D., Member of the Bioethics Commission.

Ethical Considerations and Recommendations:

Research with children is ethically distinct from other research, especially when the research in question promises no prospect of direct benefit for the participants. Competent adults can consent to accept risks for the benefit of others during research. Children are legally prohibited and ethically unable to consent to accept this burden.

Pediatric MCM research that would take place before a bioterrorism attack occurs is also ethically distinct from pediatric MCM research that would take place after an attack. Pre-event pediatric research involving MCMs involves research on a hypothetical condition with an undefined (and perhaps unknowable) likelihood of occurring.

“While the knowledge gained could be very useful in the event of an attack, we may never have – and hope never to have – occasion to use it,” Gutmann said.

By contrast, post-event testing offers a chance of directly benefiting participants and the opportunity to learn about their condition, which resulted from the attack.

Because the individual children who would be enrolled in pre-event MCM research do not stand to directly benefit from the research, the Bioethics Commission concludes that, absent extraordinary circumstances, pre-event MCM research with children is ethical only if it presents “no more than minimal risk” to study participants, where “minimal” means no greater risk than that routinely faced by a healthy child in daily life or at a medical check-up.

In keeping with its recommendation of a strict risk limit in pre-event pediatric MCM research, the Bioethics Commission called for completing all prior ethically sound testing – for example, modeling, testing in animals, and testing in the youngest adults – to assess the level of risk likely posed by pre-event pediatric MCM research. If the risk level for the oldest group of children is determined to be minimal, then progressive testing with younger and younger children should be employed, beginning with the oldest children in order to provide additional protection to younger children. This approach—called age de-escalation—would help to ensure that data from an older age group inform the research design and risk level for the next younger age group. For example, an intervention shown to be minimal risk in the youngest adults – adults 18 years of age –may make it possible to infer that a study with the oldest children of 16 and 17 years of age would present only minimal risk.

When it is impossible to design a pre-event pediatric MCM trial that poses no more than minimal risk, the proposed study must first pass muster under a “national-level review.” The Commission recommends a carefully specified set of strict preconditions before a national-level review of pre-event pediatric medical countermeasure research can proceed:

Researchers must demonstrate and reviewers must concur that it is impossible to design a minimal risk study; and

The proposed study still must pose no more than a minor increase over minimal risk to research participants, a level that still presents no substantial threat to a child’s health or well-being.

If a proposed research trial reaches this point, the Bioethics Commission recommends that reviewers be required to employ the rigorous ethical framework that is developed in its report, and cautions that it should be applied only in the rare circumstances where research risks present a minor increase over minimal.

“Current regulations are ambiguously worded and review panels that would be examining proposed pediatric MCM research would have difficulty applying them consistently. Whether the criteria outlined in the Commission’s ethical framework lead to approval or disapproval of proposed MCM research, they clarify what is at stake,” Yolanda Ali, M.B.A., Bioethics Commission Member said.

If there is an attack, post-event MCM research might offer the prospect of direct benefit to participants, or of gaining generalizable knowledge about the participants’ condition because the participants would already have been exposed to a pathogen during an attack. This is ethically distinct from pre-event research.

The Bioethics Commission recommends that post-event research be planned for and conducted when either untested or minimally tested MCMs are used to protect children in an emergency situation. In addition, the Bioethics Commission recommends that if children receive untested MCMs in an emergency in an effort to save lives, that rigorous research protections be in place.

As it examined the ethical issues surrounding research with children, the Bioethics Commission built on its previous work on the issue of protecting research participants. In December 2011, it released Moral Science: Protecting Participants in Human Subjects Research, a report that assesses the current rules and regulations that protect research participants.

“The rules that protect children are even more stringent, as they should be,” Gutmann said. “Medical countermeasure research warrants an ongoing national conversation to ensure an unwavering commitment by our society to safeguard all children both from unacceptable risks in research and through ethically sound research that promotes their health and well-being.”